Nourianz (istradefylline) / Kyowa Kirin - LARVOL DELTA

Adenosine pathway as a therapeutic target in diffuse large B cell lymphoma (ASH 2025) - "Shortstimulation with A2AR agonist (CGS-21680) causes an increase in intracellular cAMP in some cell lines(HBL-1, Ly7, Ly1) but not in others (Ly19, Ly10). This increase in cAMP can be reverted with A2ARantagonists (ciforadenant and istradefylline)...Ciforadenant at both doses increased survival in B6but not in NOD-SCID mice, with time of death considered when tumors reached 2 cm and mice wereeuthanized (Log rank (Mantel-Cox) test p=0.019). Taken together our results demonstrate that DLBCLcells are resistant to the inhibitory effects of eADO seen in normal B cells, and that A2AR antagonists areeffective for the treatment DLBCL via an immune mediated mechanism in a preclinical model of DLBCL."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • BCL2 • CD38 • CD73 • ENTPD1 • HLA-C • LY9 • NT5E • SDC1

Aberrant adenosine A2A receptor signaling in the choroid plexus drives CSF hypersecretion and ventriculomegaly in hydrocephalus. (PubMed, Nat Commun) - "Furthermore, we unveil ChP-A2AR signaling as a molecular mechanism linking brain insults with CSF hypersecretion through parallel PI3K/Akt-dependent activation of SPAK phosphorylation and NF-κB-dependent transcriptional regulation of ATP1A2. Lastly, the A2AR antagonist KW6002 protects against hydrocephalus induced by autologous blood and kaolin, offering a novel treatment for hydrocephalus by repurposing the FDA-approved A2AR antagonist istradefylline."

Journal • CNS Disorders • Ventriculomegaly • ADORA2A

Targeting the adenosine A2A receptor enhances the efficacy of low dose temozolomide in a murine glioma model (SNO 2025) - "Glioblastoma (GBM) remains one of the most aggressive brain tumors, with limited effective therapies including temozolomide (TMZ) and resistance to immunotherapy. The combination therapy significantly improved survival over sham (p = 0.0042), TMZ (p = 0.0029), and istradefylline (p = 0.0027). Our findings support the therapeutic relevance of A2AR in GBM and suggest that combining its inhibition with standard-of-care TMZ may enhance efficacy while reducing systemic toxicity."

IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • ADORA2A • IFNG • PD-1 • THY1

Biphasic actions of the adenosine A2a receptor antagonist istradefylline in mice with obstructive uropathy. (PubMed, Sci Rep) - "The adenosine A2a receptor has both anti-inflammatory and profibrotic effects. The therapeutic window by which adenosine A2a receptor antagonism may slow CKD progression is thus relatively narrow, even when employing an agent with immediate clinical applicability."

Journal • Preclinical • Chronic Kidney Disease • CNS Disorders • Fibrosis • Immunology • Movement Disorders • Nephrology • Parkinson's Disease • Renal Disease • ADORA2A • COL1A1 • TGFB1

Targeting the adenosine A2A receptor enhances the efficacy of low dose temozolomide in a murine glioma model (WFNOS 2025) - "Glioblastoma (GBM) remains one of the most aggressive brain tumors, with limited effective therapies including temozolomide (TMZ) and resistance to immunotherapy. The combination therapy significantly improved survival over sham (p = 0.0042), TMZ (p = 0.0029), and istradefylline (p = 0.0027). Our findings support the therapeutic relevance of A2AR in GBM and suggest that combining its inhibition with standard-of-care TMZ may enhance efficacy while reducing systemic toxicity."

IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • ADORA2A • IFNG • PD-1 • THY1

Terpenes from Cannabis sativa relieve neuropathic pain in mice via the Adenosine A2a Receptor expressed in Pax2+ spinal inhibitory interneurons (Neuroscience 2025) - "By utilizing CRISPR knockdown and the small molecule inhibitor istradefylline, we showed that terpenes act in CIPN through the activation of the Adenosine A2a Receptor (A2aR) in the spinal cord...Taken together, we show that terpenes have antinociceptive effects in neuropathic pain via the A2aR on Pax2+ inhibitory interneurons in mouse spinal cord. With this work, we aim to identify the detailed mechanism by which terpenes relieve neuropathic pain, and establish a scientific basis for their use as a novel non-opioid pain therapeutic."

Preclinical • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • ADORA2A • PAX2

Alzheimer s disease hypoperfusion is driven by an imbalance between A2A and A1 adenosine receptors (Neuroscience 2025) - " Aged (15-month-old) female 3xTg-AD and C57BL/6J mice were treated with istradefylline (A2AR antagonist - 2 mg/kg/day, IP) or tecadenoson (A1R agonist - 15 μg/kg, IP) for 7 days... Although agonism of A1R were not sufficient to restore A2AR/A1R balance, blockage of A2AR were. We are considering a different pharmacological approach to improve A1R, to mimic the improvements observed with A2AR blockage."

Alzheimer's Disease • CNS Disorders • TJP1

Cisplatin-induced disruption in reward-motivated behavior is associated with microglial reactivity and impaired medium spiny neuron morphology in the striatum (Neuroscience 2025) - "Our preliminary data also indicate that the A2A receptor antagonists KW6002 and caffeine attenuate cisplatin-induced nesting impairments...Our findings suggest that cisplatin impairs nesting-related reward-motivated behavior, striatal MSN morphology, and that microglial activation may be associated with emotive dysfunction in CICI. In summary, our studies identify novel therapeutic targets that can be targeted to improve the quality of life for cancer survivors."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • ADORA2A • CD68

Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial. (PubMed, JMIR Res Protoc) - P1/2 | "These aims will provide crucial data regarding the preliminary safety and feasibility of this paired intervention and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS."

Clinical • Clinical protocol • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Levodopa-induced dyskinesia in Parkinson's disease: an updated review of pharmacological treatments. (PubMed, Front Aging Neurosci) - "Despite decades of investigation, only amantadine has been established as the standard FDA-approved treatment, while istradefylline provides a complementary non-dopaminergic option. Most other candidate agents-including memantine, clozapine, and serotonergic or noradrenergic modulators-have shown inconsistent efficacy or safety limitations, underscoring persistent translational challenges between preclinical promise and clinical outcomes...Potential complementary pathways, including Traditional Chinese Medicine (TCM), are also briefly noted as alternative directions. By linking mechanistic insights with therapeutic evidence, this review provides an updated framework for optimizing LID management and guiding future research directions."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Adenosine A2A receptor modulation affects the development of depressive-like behaviour and dopamine D2 receptor availability in rats exposed to repeated social defeat. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Our study showed that the treatment with either an A2AR agonist or an A2AR antagonist prevented the development of depressive-like behaviour, and reduced the availability of D2 receptor in the striatum after exposure to RSD most likely by modulating the receptor affinity."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • ADORA2A • DRD2

Combining Low Oxygen Therapy and an Adenosine A2a Receptor Antagonist to Improve Functional Mobility After Spinal Cord Injury (clinicaltrials.gov) - P1/2 | N=40 | Not yet recruiting | Sponsor: Randy Trumbower, PT, PhD | Trial completion date: Jun 2027 ➔ Jun 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • CNS Disorders • Musculoskeletal Diseases • Orthopedics

Istradefylline for Freezing of Gait in Parkinson's Disease: A Systematic Review and Meta-Analysis (MDS Congress 2025) - "Istradefylline demonstrated a modest improvement in UPDRS scores and a more pronounced effect on FOG-Q scores, suggesting potential benefits for FOG in PD. These findings highlight the need for more extensive randomized controlled trials to confirm istradefylline's efficacy in managing gait disturbances in PD patients. Figure 1"

Retrospective data • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • ADORA2A

Parkinsonism after Post-Anoxic Brain Injury (MDS Congress 2025) - "Carbidopa-levodopa and istradefylline offered little benefit for FOG. Patient experienced partial improvement in gait with amantadine... Parkinsonism is a rare manifestation that may be encountered in post-anoxic patients with basal ganglia injury. Differences in symptoms and response to medications may be due to extent of basal ganglia damage. DaT scan may be considered for further verification of parkinsonism in anoxia."

CNS Disorders • Movement Disorders • Parkinson's Disease • Vascular Neurology

Cognitive Effects of Istradefylline in Parkinson's Disease: A 26-Week Open-Label Pilot Study (MDS Congress 2025) - "These findings provide preliminary evidence that istradefylline may improve broad aspects of cognition in PD, particularly in executive function, attention, and memory. While suggestive, these results require confirmation in a randomized and controlled trial."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease • ADORA2A

Adenosine A2A receptor activation in the nucleus accumbens decreases motivation for wheel running in male mice. (PubMed, Psychopharmacology (Berl)) - "These findings demonstrate that, in male mice, A2A receptor activation selectively suppressed the appetitive component of wheel-running motivation, whereas A2A receptor blockade did not. Together, our results highlight the crucial role of NAc A2A receptors in regulating motivation for wheel running and suggest the potential therapeutic application of A2A receptor agonists for treating maladaptive behavioral over-engagement."

Journal • Preclinical • CNS Disorders • Psychiatry • ADORA2A

Endothelial adenosine receptor 2A loss alleviates diabetic vascular calcification by blocking CREB1-SNAI1-driven EndMT. (PubMed, Pharmacol Res) - "Deletion of endothelial Adora2a or pharmacologic inhibition of ADORA2A with KW6002 attenuated EndMT, osteogenic differentiation, and calcium deposit in diabetic aortas of Ins2Akita/+ mice...Collectively, our results reveal a previously unrecognized role of endothelial ADORA2A inactivation in attenuating diabetic VC via modulation of EndMT. These insights offer a compelling mechanistic rationale for leveraging ADORA2A antagonists as promising therapeutic agents against diabetic VC."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • ADORA2A • CREB1 • SNAI1

Impact of Adjunctive Istradefylline on Dyskinesia Onset in Patients with Parkinson's Disease Exhibiting Wearing-Off: An Open-Label Randomized Controlled Trial. (PubMed, Neurol Ther) - "Adjunctive IST showed no difference in the onset of dyskinesia compared with adding another or increasing the dose of other anti-PD drugs, and displayed equivalent efficacy and tolerability, while maintaining a lower LEDD in this long-term study of patients with PD exhibiting WO. These findings support the use of adjunctive IST as a viable treatment option for patients with PD exhibiting WO."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Camptocormia in Parkinson's disease: state of the art and future directions. (PubMed, J Neurol) - "There is no consensus for treatment of PD-related camptocormia, although some nonpharmacological (e.g., backpack weight, back extensors and physiotherapy), pharmacological (e.g., levodopa, istradefylline and botulinum toxin) and surgical approaches (surgical corrections and deep brain stimulation) were elaborated upon with variable effects...Of all these publications, only 27 (19.6%) were reviews, and more than half of which (15 reviews) focused on some characteristics of camptocormia (e.g., surgical treatment, deep brain stimulation, and prevalence or etiology) but did not elucidate on all its complex aspects. The present narrative review aims to describe different aspects of camptocormia ranging from its prevalence to the pathophysiology and treatment possibilities and provide a comprehensive image of this disorder."

Journal • Review • Back Pain • CNS Disorders • Dystonia • Movement Disorders • Musculoskeletal Pain • Myositis • Osteoarthritis • Pain • Parkinson's Disease • Seronegative Spondyloarthropathies

Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (Peff) and Fraction Absorbed (fa). (PubMed, Mol Pharm) - "The correlations were subsequently used to estimate Peff and fa for six test APIs: acetaminophen, voriconazole, fedratinib, voxelotor, lemborexant, and istradefylline. The projected Peff and fa values for the test APIs aligned well with literature permeabilities derived using other methods and clinical pharmacokinetic studies, respectively. This work highlights the usefulness of cMdr1 KO MDCK cells in permeability classification, especially for highly permeable APIs, and supports its broader use in both research and regulatory contexts."

Journal • ABCB1

Characterization of mice with cell type-specific Gnal loss of function provides insights on GNAL-linked dystonia. (PubMed, Neurobiol Dis) - "Hyperactivity is not further enhanced by psychostimulant drugs (cocaine, D-amphetamine, methylphenidate) or a selective A2 agonist, KW6002, but is paradoxically reduced by caffeine. Our study identifies specific roles of Gαolf downstream of D1 and A2A receptors in the control of motor behavior and drug responses, highlighting their respective individual contribution in dysfunctional striatal signaling, including dystonia."

Journal • Preclinical • CNS Disorders • Dystonia • Movement Disorders • ADORA2A

Adenosine A2A Receptor in the Choroid Plexus Modulates Ischemia-Reperfusion Injury in the Cortex. (PubMed, J Am Heart Assoc) - "Our findings highlight the A2AR in ChP as a pivotal regulator of I/R injury in the cortex, modulating ChP gateway activity and CSF production, providing a promising therapeutic target for stroke management."

Journal • Cardiovascular • CNS Disorders • Reperfusion Injury • Vascular Neurology • ADORA2A • CCL2 • CXCL1 • CXCL10 • ICAM1

Adenosine 2A Receptor Antagonism and AIH in ALS (clinicaltrials.gov) - P1/2 | N=40 | Recruiting | Sponsor: University of Florida | Trial completion date: Dec 2025 ➔ May 2026

Trial completion date

Istradefylline for Parkinson Disease With Cognitive Impairment (clinicaltrials.gov) - P2 | N=15 | Completed | Sponsor: Virginia Commonwealth University | Active, not recruiting ➔ Completed | N=10 ➔ 15

Enrollment change • Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease

Experimental and computational approaches for evaluating molecule interactions with equilibrative nucleoside transporters 1 and 2. (PubMed, J Pharmacol Exp Ther) - "This resulted in the identification of the Food and Drug Administration-approved drugs isradipine, avanafil, and istradefylline as inhibitors of ENT1. We have screened over 1600 diverse molecules, allowing us to build machine learning models that in turn were further used to make predictions to validate the models. Our combined experimental and machine learning approach resulted in the identification of multiple Food and Drug Administration-approved medications as inhibitors of ENT1 or ENT2."

Journal • Infectious Disease • Oncology • SLC29A1 • SLC29A2